Hepatitis C virus (HCV) infects 170 million people worldwide, and is a leading cause of liver-related mortality due to development of cirrhosis and hepatocellular carcinoma. Treatment of chronic HCV infection is now possible with combinations of oral, directly acting antiviral agents (DAAs), which do not require exogenous injectable interferon (IFN) to achieve HCV eradication. Treatment failure with DAA therapy typically occurs due to HCV relapse after treatment, although mechanisms are poorly understood. Furthermore, the necessary duration of treatment required to achieve a sustained virologic response (SVR), synonymous with HCV eradication, differs between people, and may be influenced by host immunity. The goal of this project is to discover host immune correlates and mechanisms of treatment outcome during IFN-free DAA therapy for HCV. To accomplish this, the applicant will utilize clinical samples collected during therapy to assess differences between subjects who achieve SVR versus relapse in markers of (1) immune activation and interferon sensitivity in peripheral blood, (2) the liver proteome before and after treatment, with analysis using bioinformatics platforms, and (3) in vitro sensitivity of lymphocytes and monocytes during DAA therapy to exogenous immune stimulation, asking whether such stimulation at the end of treatment could prevent relapse. The applicant, Dr. Meissner, is a physician-scientist in the Division of Infectious Diseases at the Medical University of South Carolina, with a secondary appointment in the Department of Microbiology and Immunology. His long-term career goal is to become an independent investigator studying mechanisms of inter-individual immune variability in response to chronic viral infections, in order to better understand disease progression and differential response to therapies. To facilitate his transition to investigative independence, he is seeking to broaden the multidisciplinary nature of his investigations by developing expertise in tissue proteomics, in vitro study of immunity, and use of bioinformatic tools. The environment for the success of Dr. Meissner is provided by (1) a multi-disciplinary team with a track record of mentoring and expertise needed to support the project, (2) departmental and divisional support with protected time to develop a career as a physician scientist, (3) availability of a unique set f clinical samples collected during IFN-free therapy for chronic HCV infection, and (4) active clinical participation in an Infectious Diseases clinic providing care to patients infected with HC alone or co-infected with HCV and the human immunodeficiency virus (HIV). Identification of correlates and mechanisms of treatment relapse during DAA therapy for HCV infection will provide timely contributions to an active clinical field that is changing dynamically with new treatment options. This training will enable Dr. Meissner to achieve his long-term goal of becoming an independent investigator leading multidisciplinary efforts to study variability in the host response to chronic viral infections including HCV, HIV, and hepatitis B virus, with the aim of understanding and improving clinical outcomes.